Process for the preparation of β-lactam compounds

ABSTRACT

A process for the preparation of a β-lactam having the partial structure (I): ##STR1## wherein R 1  is an acyl group, which process comprises treating an imine having the partial structure (II): ##STR2## with a nucleophilic derivative of formamide.

This invention relates to a chemical process for the preparation ofβ-lactam compounds, and in particular for the introduction of aformamido substituent into a β-lactam having an acylamino side chain.Certain of the substituted β-lactam compounds produced by this processare antibacterial agents; others are useful as intermediates forproducing such agents. Each of these groups is described below.

The present invention provides a process for the preparation of aβ-lactam having the partial structure (I): ##STR3## wherein R¹ is anacyl group, which process comprises treating an imine having the partialstructure (II) ##STR4## with a nucleophilic derivative of formamide.

Suitably the acyl group for R¹ is a carboxylic acyl group. Othersuitable acyl groups for R¹ include sulphonyl and phosphonyl groups.

Suitable nucleophilic derivatives of formamide include N-silyl,N-stannyl and N-phosphorylated derivatives.

By the term `N-silyl derivative` of formamide we mean the product ofreaction of the amino group of formamide with a silylating agent such asa halosilane or a silazane of the formula:

L₃ Si.U; L₂ Si.U₂ ; L₃ Si.NL₂ ;

L₃ Si.NH.SiL₃ ; L₃ Si.NH.COL; L₃ Si.NH.CO.NH.SiL₃ ;

LNH.CO.NH.SiL₃ ; ##STR5## wherein U is a halogen and the various groupsL which may be the same or different, each represents hydrogen or alkyl,alkoxy, aryl, or aralkyl. Preferred silylating agents are silylchlorides, particularly trimethylchlorosilane.

The term `N-stannyl derivative` of formamide includes the product ofreaction of the amino group of formamide with a stannylating agent suchas a halostannane of formula:

    L.sub.3 SnU

wherein L and U are as defined hereinbefore.

The term `N-phosphorylated` derivative of formamide is intended toinclude compounds wherein the amino group of formamide is substitutedwith a group of formula:

    --P.R.sub.a R.sub.b

wherein R_(a) is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy or dialkylamino group, R_(b) is the same as R_(a) oris halogen or R_(a) and R_(b) together form a ring.

Other suitable nucleophilic derivatives of formamide include ##STR6##wherein R' and R" may be the same or different and each represent a C₁₋₆alkyl group or R' and R" together represent a C₂₋₄ alkylene di-radical.

Preferably the nucleophilic derivative of formamide is aN,N-bis(tri-loweralkylsilyl)formamide, in particularN,N-bis(trimethylsilyl)formamide.

Suitable solvents in which the reaction may be performed include forexample, dioxan, tetrahydrofuran, dimethylformamide, andhexamethylphosphoramide. The reactions are generally carried out underan inert atmosphere and at moderate to low temperatures ie in the range-100° C. to +30° C. The course of the reaction may be followed byconventional methods such as thin layer chromatography and terminatedwhen an optimum quantity of product is present in the reaction mixture.

Subsequent to the reaction it may be necessary to regenerate theformamido group from any derivative; suitable methods include thoseknown in the art such as, for example, acid or base hydrolysis ortreatment with a metal ion such as mercury, silver, thallium, lead orcopper.

In a further aspect the present invention provides a process for thepreparation of a compound of formula (III) or a salt thereof: ##STR7##wherein R¹ is as defined hereinbefore; R² is hydrogen or a readilyremovable carboxyl protecting group; and Y is: ##STR8## wherein Y⁰ issulphur, SO or SO₂, Y¹ is oxygen, sulphur, SO, SO₂ or --CH₂ -- and Zrepresents hydrogen, halogen, or an organic group such as C₁₋₄ alkoxy,--CH₂ Q or --CH═CH--Q wherein Q represents hydrogen, halogen, hydroxy,mercapto, cyano, carboxy, carbamoyloxy, carboxylic ester, C₁₋₄ alkyloxy,acyloxy, aryl, a heterocyclyl group bonded via carbon, aheterocyclylthio group or a nitrogen containing heterocyclic groupbonded via nitrogen, which process comprises treating an intermediateimine of formula (IV): ##STR9## wherein any reactive groups may beprotected; R¹ and Y are as hereinbefore defined and wherein any reactivegroups may be protected; and R^(x) is a readily removable carboxyprotecting group; with a nucleophilic derivative of formamide andthereafter, if necessary, carrying out one or more of the followingsteps:

(i) removing any protecting groups;

(ii) converting a group R^(x) to a group R² ;

(iii) converting one group Z into a different group Z;

(iv) converting the product into a salt.

When used herein the term `halogen` unless otherwise defined is suitablyfluorine, chlorine, bromine and iodide, preferably chlorine and bromine.

When used herein the term 'carboxylic ester` unless otherwise definedsuitably include C₁₋₆ alkyl esters.

When used herein the term `acyloxy` unless otherwise defined suitablyincludes C₁₋₆ alkylcarbonyloxy groups.

When used herein the term `aryl` unless otherwise defined suitablyincludes phenyl and naphthyl, preferably phenyl, optionally substitutedwith up to five halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo(C₁₋₆) alkyl,hydroxy, amino, carboxy, C₁₋₆ alkoxycarbonyl, or C₁₋₆alkoxycarbonyl-(C₁₋₆)-alkyl groups.

When used herein the term `heterocyclyl` unless otherwise definedsuitably includes single or fused rings comprising up to four heteroatoms in the ring selected from oxygen, nitrogen, and sulphur andoptionally substituted with up to three halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, halo-(C₁₋₆)-alkyl, hydroxy, amino, carboxy, C₁₋₆ alkoxycarbonyl,C₁₋₆ alkoxycarbonyl(C₁₋₆) alkyl, aryl, oxo, carboxy(C₁₋₆)alkyl,carbamoyl-(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, substituted amino(C₁₋₆) alkylor sulphonyl(C₁₋₆)alkyl groups.

When used herein the term `lower` indicates that the group contains 1 to6 carbon atoms.

Suitably Y is: ##STR10## wherein Y² is oxygen, sulphur or --CH₂ -- and Zis as hereinbefore defined.

Preferred values for Y in the compounds of formula (III) are--S--C(CH₃)₂ -- and --S--CH₂ --C(CH₂ Q)═, ie when the compound offormula (III) is a derivative of a penicillin or cephalosporin.

A particularly preferred value for Y is --S--C(CH₃)₂ --.

A further preferred value for Y is --S--CH₂ --CZ═ wherein Z is ashereinbefore defined.

The acyl group for R¹ is suitably an acyl group of an antibacteriallyactive penicillin or cephalosporin. Suitable groups R¹ include those offormula R³ CO-- as defined below.

The acyl group for R¹ is also suitably a removable amino-protecting acylgroup.

Examples of removable amino-protecting acyl groups for R¹ includebenzyloxycarbonyl optionally substituted in the phenyl ring by one ortwo substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,halogen or nitro; C₁₋₄ alkoxycarbonyl, for example tert-butoxycarbonyl;allyloxycarbonyl; or trichloroethoxycarbonyl.

Suitable removable amino-protecting acyl groups R¹ are those well-knownin the art which may be removed under conventional conditions withoutdisruption of the remainder of the molecule.

Preferred examples of removable amino-protecting acyl groups within R¹include those listed above which are removable under acid conditionsoptionally in the presence of a group IIb metal.

It will be appreciated that removal of an amino protecting acyl group R¹gives the β-amino derivative of the β-lactam.

Those compounds of the formula (III) wherein R² is a readily removablecarboxyl protecting group or a non-pharmaceutically acceptable salt, areprimarily useful as intermediates in the preparation of compounds of theformula (III) wherein R² is a free carboxyl group or a pharmaceuticallyacceptable salt thereof. The conversion referred to above may beaccomplished by procedures per se well known in the art. Also includedwithin the readily removable carboxyl protecting groups R² arepharmaceutically acceptable in vivo hydrolysable ester groups.

The antibacterial compounds produced by the process of the presentinvention are formulated into pharmaceutical compositions according totechniques per se known in the art and are administered by conventionalroutes and dosage rates; for example, as disclosed in U.S. patentapplication Ser. No. 401,266 and European Patent Application No.8230382.1 (publication No. 0071395) which are incorporated herein byreference.

Examples of suitable pharmaceutically acceptable in vivo hydrolysableester groups include those which break down readily in the human body toleave the parent acid or its salt. Suitable ester groups of this typeinclude those of part formula (i), (ii) and (iii): ##STR11## whereinR^(a) is hydrogen, methyl, or phenyl, R^(b) is C₁₋₆ alkyl, C₁₋₆ alkoxyor phenyl; or R^(a) and R^(b) together form a 1,2-phenylene groupoptionally substituted by one or two methoxy groups; R^(c) representsC₁₋₆ alkylene optionally substituted with a methyl or ethyl group--R^(d)and R^(e) independently represent C₁₋₆ alkyl; R^(f) represents C₁₋₆alkyl.

Examples of suitable in vivo hydrolysable ester groups include forexample acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl,α-acetoxyethyl and α-pivaloyloxyethyl groups; alkoxycarbonyloxyalkylgroups such as ethoxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl;dialkylaminoalkyl especially di-loweralkylamino alkyl groups; such asdimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl ordiethylaminoethyl; lactone groups such as phthalidyl anddimethoxyphthalidyl; and esters linked to a second β-lactam antibioticor to a β-lactamase inhibitor.

Suitable readily removable carboxyl protecting groups for the group--CO₂ R² in formula (III) and --CO₂ R^(x) in formula (IV) include saltand ester derivatives of the carboxylic acid. The derivative ispreferably one which may readily be cleaved.

Suitable ester-forming carboxyl-protecting groups are those which may beremoved under conventional conditions. Such groups for R² and R^(x)include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl,4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl,t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl,2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl,tetrahydropyran-2-yl, pentachlorophenyl, acetonyl,p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl orphosphorus-containing group, an oxime radical of formula --N═CHR^(o)where R^(o) is aryl or heterocyclic, or an in vivo hydrolysable esterradical such as defined above.

The carboxyl group may be regenerated from any of the above esters byusual methods appropriate to the particular R² or R^(x) group, forexample, acid--and base--catalysed hydrolysis, or byenzymically-catalysed hydrolysis, or by hydrogenolysis.

Suitable pharmaceutically acceptable salts of the carboxy group of thecompound of formula (III) include metal salts eg aluminium, alkali metalsalts such as sodium or potassium, alkaline earth metals salts such ascalcium or magnesium and ammonium or substituted ammonium salts, forexample those with lower alkylamines such as triethylamine,hydroxy-lower alkylamines such as 2-hydroxyethylamine,bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine,cycloalkylamines such as dicyclohexylamine, or with procaine,dibenzylamine, N,N-dibenzylethylene-diamine, 1-ephenamine,N-ethylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine,N,N'-bisdehydro-abietylamine, ethylenediamine, or bases of the pyridinetype such as pyridine, collidine or quinoline, or other amines whichhave been used to form salts with known penicillins and cephalosporins.Other suitable salts include the lithium and silver salt.

Suitable values for Q in the compounds of the formula (III) include theacetoxy, heterocyclylthio group, and nitrogen containing heterocyclicgroup bonded via nitrogen.

More suitably Q represents the acetoxy or heterocyclylthio group.

The heterocyclylthio group may suitably be represented by the formula:

    --S--Het

wherein `Het` is a five or six membered heterocyclic ring containingfrom 1 to 4 atoms selected from N, O, and S unsubstituted or substitutedwith one or two groups selected from C₁₋₆ alkyl, C₁₋₆ alkoxy,hydroxyalkyl, C₁₋₆ alkenyl, alkoxyalkyl, carboxyalkyl, sulphonylalkyl,carbamoylalkyl, trifluoromethyl, hydroxy, halogen, oxo, optionallysubstituted aminoalkyl, and carboxy-alkyl or two substituents may belinked to form the residue of a heterocyclic or carbocyclic ring.

Examples of the group `Het` include unsubstituted and substitutedimidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl,thiatriazolyl, oxazolyl, triazinyl and oxadiazolyl.

Suitable groups `Het` include unsubstituted and substituted1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; oxazolyl; thiazolyl;1,3,4-oxadiazolyl; 1,3,4-thiadiazolyl; or 1,2,4-thiadiazolyl. Preferablythe heterocyclylthio group is 1-methyl-1H-tetrazol-5-ylthio,2-methyl-1,3,4-thiadiazol-5-ylthio, 1-carboxymethyl-1H-tetrazol-5-ylthioor 6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3-ylthio.

The nitrogen containing heterocyclic group bonded via nitrogen issuitably a pyridinium group unsubstituted or substituted with one or twogroups selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyalkyl, C₁₋₆alkenyl, alkoxyalkyl, carboxyalkyl, sulphonylalkyl, carbamoylmethyl,carbamoyl, trifluoromethyl, hydroxy, halogen, oxo, aminoalkyl, or twosubstituents on adjacent carbon atoms may form the residue of acarbocyclic ring.

Preferred compounds produced by the process of this invention can berepresented by the formula (V) or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof: ##STR12## wherein Y is as definedwith respect to formula (III); and R₃ is a group such that R₃ --CO--NH--is an acylamino group in particular that as found in antibacteriallyactive penicillins or cephalosporins.

Suitable groups R₃ CO-- for inclusion in the compounds of the formula(V) include those of the sub-formulae (a)--(e): ##STR13## wherein n is0, 1 or 2; m is 0, 1 or 2; A₁ is C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₃₋₆ cycloalkyl, cyclohexenyl, cyclohexadienyl, an aromatic group, suchas phenyl, substituted phenyl, thienyl, pyridyl, an optionallysubstituted thiazolyl group a C₁₋₆ alkylthio group or C₁₋₆ alkyloxy; Xis a hydrogen or halogen atom, a carboxylic acid, carboxylic ester,sulphonic acid, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido,acylamino, heterocyclylamino, guanidino or acylureido group; A₂ is anaromatic group such as a phenyl, a 2,6-dimethoxyphenyl,2-alkoxy-1-naphthyl, 3-arylisoxazolyl, 3-aryl-5-methylisoxazolyl group asubstituted alkyl group, or a substituted dithietane; X₁ is a CH₂ OCH₂,CH₂ SCH₂ or (CH₂)_(n) group; X₂ is an oxygen or suphur atom; A₃ is anaryl or heteroaryl group such as phenyl, substituted phenyl oraminothiazolyl; and A₄ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,arylaminocarbonyl, C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkanoyl, C₁₋₆alkoxycarbonyl, C₂₋₆ alkenyl, carboxy C₁₋₆ alkyl, C₁₋₆ alkylsulphonyland di-C₁₋₆ alkylphosphatomethyl.

More suitably A₁ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, cyclohexenyl,cyclohexadienyl, phenyl, hydroxyphenyl, thienyl or pyridyl group; and Xis a hydrogen or halogen atom, a carboxylic acid, carboxylic ester,azido, tetrazolyl, hydroxy, acyloxy, amino, ureido, guanidino oracylureido group.

Other more suitable groups A₁ include dihydroxyphenyl,di(C₁₋₆)alkanoyloxyphenyl such as diacetoxyphenyl anddi(C₁₋₆)alkoxycarbonylphenyl, such as diethoxycaronyloxyphenyl.

Favoured groups R³ for inclusion in the compounds of the formula (V)include those of the sub-formula (f) and (g): ##STR14## wherein R⁴ is aphenyl, thienyl or phenoxy group; R⁵ is a hydrogen atom or methyl group;R⁶ is a phenyl, substituted phenyl, substituted thiazolyl, thienyl orcyclohexadienyl group; and R⁷ is a hydroxyl, carboxylic acid group orlower alkyl or phenyl, tolyl or indanyl ester thereof, amino or asubstituted amino group.

Suitably the substituted phenyl group for R⁶ is a phenyl groupsubstituted with up to three groups selected from C₁₋₆ alkyl, phenyl,halogen, C₁₋₆ alkoxy, amino, nitro, hydroxy, C₁₋₆ alkylamido, C₁₋₆alkylcarbonyloxy, carboxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkoxycarbonyloxy,halo(C₁₋₆)alkyl, oxo(C₁₋₆)alkyl, C₁₋₆ alkylcarbonyl, aryloxy,aralkyloxy, arylcarbonyl, C₁₋₆ alkylamino or di(C₁₋₆)alkylamino.

Preferably R⁶ is a phenyl, p-hydroxyphenyl, thienyl or cyclohexadienylgroup.

Other preferred groups R⁶ include 3,4-dihydroxy-phenyl and3,4-diacetoxyphenyl.

Preferably R⁷ is a substituted amino group.

More preferably the substituted amino group R⁷ is a ureido, acylamino oracylureido group.

One suitable sub-group of compounds produced by the process of thepresent invention provides a compound of formula (VI) or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof:##STR15## wherein Y is as defined with respect to formula (III) and R⁸is phenyl, substituted phenyl, cyclohexenyl, cyclohexadienyl, or a 5- or6-membered heterocyclic ring containing up to three hetero-atomsselected from oxygen, sulphur or nitrogen, optionally substituted withhydroxy, amino, halogen, substituted amino or C₁₋₆ alkoxy; R⁹ ishydrogen, a C₁₋₆ alkyl group or substituted C₁₋₆ alkyl group and R¹⁰ isan optionally substituted 5- or 6-membered heterocyclic group containingone or two nitrogen heteroatoms; or R⁹ and R¹⁰ together with thenitrogen atom to which they are attached form an optionally substitutedfive- or six-membered heterocyclic group containing one or two nitrogenheteroatoms.

Suitably the substituted phenyl group for R⁸ is a phenyl groupsubstituted with up to three groups selected from C₁₋₆ alkyl, phenyl,halogen, C₁₋₆ alkoxy, amino, nitro, hydroxy, C₁₋₆ alkylamido, C₁₋₆alkylcarbonyloxy, carboxy, C₁₋₆ alkoxycarbonyl, halo (C₁₋₆)alkyl,oxo(C₁₋₆)alkyl, C₁₋₆ alkylcarbonyl, aryloxy, aralkyloxy, arylcarbonyl,C₁₋₆ alkylamino or di(C₁₋₆)alkylamino.

In formula (VI), the group R⁸ is preferably phenyl, 4-hydroxyphenyl,3,4-di(C₁₋₆ -alkylcarbonyloxy)-phenyl, 3,4-dihydroxyphenyl, 2-thienyl,3-thienyl or 2-amino-4-thiazolyl.

Particularly preferred groups R⁸ are 3,4-dihydroxyphenyl and3,4-diacetoxyphenyl.

Suitably R⁹ is hydrogen.

Suitable substituents for the 5- or 6-membered heterocyclic group of R¹⁰or R⁹ and R¹⁰ together include the optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl or cycloalkenyl group; optionallysubstituted phenyl, oxo; the hydroxy group optionally substituted byalkyl, alkenyl, cycloalkyl, phenyl, pyridyl, pyrimidyl or benzyl; theoptionally substituted mercapto group, the alkylsulphonyl group; thesubstituted imino group; or the amino group optionally substituted by analkyl, alkenyl, cycloalkyl, phenyl, substituted phenyl or benzyl group.Alternatively two substituents on the ring may form the residue of afurther carbocyclic or heterocyclic ring.

Preferred values for Y in the compounds of formulae (V) and (VI) are--S--C(CH₃)₂ -- and --S--CH₂ C(CH₂ Q)═, wherein Q is hereinbeforedefined ie when the compounds of formulae (V) and (VI) are derivativesof a penicillin or cephalosporin.

The carbon atom marked * in formulae herein is asymmetric so that thecompounds may exist as two optically active diastereoisomers. In generalthat prepared from the D-side chain exhibits the highest antibacterialactivity and accordingly the D compound or the DL mixtures arepreferred, with the D compound being particularly preferred.

Preferred compounds within formula (V) are the penicillin derivatives offormula (VII) or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof: ##STR16## wherein R¹¹ is phenyl, substitutedphenyl, cyclohexenyl, cyclohexadienyl, or a 5- or 6-memberedheterocyclic ring containing up to three heteratoms selected fromoxygen, sulphur or nitrogen, optionally substituted with hydroxy, amino,halogen or C₁₋₆ alkoxy, R¹² is hydrogen or C₁₋₆ alkyl and R¹³ is anoptionally substituted five- or six-membered heterocyclic groupcontaining one or two nitrogen heteroatoms; or R¹² and R¹³ together withthe nitrogen atom to which they are attached form an optionallysubstituted five- or six-membered heterocyclic group containing one ortwo nitrogen heteroatoms.

In formula (VII) the group R₁₁ is preferably phenyl, 4-hydroxyphenyl,2-thienyl, 3-thienyl, 2-amino-4-thiazolyl, 3,4-dihydroxyphenyl or3,4-diacetoxyphenyl.

Particularly preferred groups R¹¹ include 3,4-dihydroxyphenyl and3,4-diacetoxyphenyl.

Suitable substituents for the five- or six-membered heterocyclic groupof R¹³ or R¹² and R¹³ together include the alkyl, alkenyl, alkynyl,cycloalkyl or cycloalkenyl group, optionally substituted phenyl, oxo,the hydroxy group optionally substituted by alkyl, alkenyl, cycloalkyl,phenyl, pyridyl, pyrimidyl or benzyl, the optionally substitutedmercapto group, the alkylsulphonyl group, the substituted imino group,or the amino group optionally substituted by an alkyl, alkenyl,cycloalkyl, phenyl, substituted phenyl or benzyl group. Alternativelytwo substituents on the ring may form the residue of a furthercarbocyclic or heterocyclic ring.

Preferably R¹² is hydrogen.

One particularly preferred sub-group produced by the process of thepresent invention provides a compound of formula (VIII) or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof:##STR17## wherein R⁸ and Y are as defined with respect to formula (VI)and R¹⁴ represents hydrogen, C₁₋₆ alkyl, substituted alkyl, aryl, oraralkyl; R¹⁵ and R¹⁶ are the same or different and represent hydrogen,C₁₋₆ alkyl, substituted alkyl, halogen, amino, hydroxy or C₁₋₆ alkoxy orR¹⁵ and R¹⁶ form the residue of 5- or 6-membered carbocyclic orheterocyclic ring.

Suitable values for Y in the compounds of formula (VIII) are--S--C(CH₃)₂ -- and --S--CH₂ --C(CH₂ Q)=wherein Q is as hereinbeforedefined.

Preferably Y in the compounds of formula (VIII) is --S--C(CH₃)₂ --.

Preferred compounds within formula (VIII) are the penicillin derivativesof formula (IX) or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof: ##STR18## wherein R¹¹, R¹⁴, R¹⁵ and R¹⁶ areas hereinbefore defined.

Suitable C₁₋₆ alkyl groups for the groups R¹⁴, R¹⁵ and R¹⁶ in formula(VIII) and formula (IX) include methyl, ethyl, n- and iso-propyl, n-,sec-, iso- and tert-butyl. Preferably R¹⁴ is ethyl. Preferably R¹⁵ andR¹⁶ are hydrogen.

A further preferred subgroup of compounds produced by the process of thepresent invention are the compounds of formula (X) or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof: ##STR19## whereinR³ and Y¹ are as hereinbefore defined; and Q² represents acetoxy; agroup --SHet, wherein Het is as hereinbefore defined; or Q² represent asubgroup of formula (h): ##STR20## wherein R_(q) and R_(p) may be thesame or different and each represents hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,hydroxy-alkyl, C₁₋₆ alkenyl, alkoxyalkyl, carboxyalkyl, sulphonylalkyl,carbamoylalkyl, carbamoyl, trifluoro-methyl, hydroxy, halogen, andaminoalkyl or R_(q) and R_(p) form the residue of a carbocyclic ring.

Suitable values of R³ CO-- within formula (X) are those of formulae (a)to (g) as hereinbefore defined with reference to formula (V).

Suitable groups `Het` within formula (X) include substituted andunsubstituted 1,2,3-triazolyl; 1,2,4-triazolyl; tetrazolyl; oxazolyl;thiazolyl; 1,3,4-oxadiazolyl; 1,2,4-triazinyl; 1,3,4-thiadiazolyl or1,2,4-thiadiazolyl. Preferably the groups 'S Het is1-methyl-1H-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio,1-carboxymethyl-1H-tetrazol-5-ylthio or6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3-ylthio.

Suitably R_(q) represents hydrogen.

Suitably R_(p) represents hydrogen, sulphonylalkyl or carbamoy,preferably the substituent R_(p) is in the 4-position.

Suitably Y¹ is oxygen or sulphur.

More suitably Y¹ is oxygen.

More suitably Y¹ is sulphur.

Preferably R³ within formula (X) is a subgroup of formula (j): ##STR21##wherein R⁸, R¹⁴,R¹⁵ and R¹⁶ are as hereinbefore defined with referenceto formula (VIII).

The imine of formula (IV) may suitably be prepared by treatment of acompound of formula (XI). ##STR22## wherein R¹ and R^(x) are ashereinbefore defined and wherein any reactive groups may be protected;and R¹⁷ is C₁₋₆ alkyl, aryl, or benzyl with a metal ion such as mercury,silver, thallium, lead or copper.

Suitable examples of the alkyl group for R¹⁷ include C₁₋₆ alkyl groupssuch as methyl, ethyl, n-, or iso-propyl, and n-, sec-, iso-, ortert-butyl groups.

A preferred alkyl group for R¹⁷ is methyl.

Suitable examples of the aryl group R¹⁷ include phenyl, optionallysubstituted with C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen or nitro. Preferredaryl groups for R¹⁷ include phenyl, o-, m- or p-methylphenyl, or o-, m-or p-nitrophenyl, in particular p-methylphenyl.

The preferred metal ion for use in the above process is the mercuricion, aptly in the form of mercuric acetate.

Suitably such a reaction is performed at moderate to low temperature forexample -10° C. to +30° C., and preferably ambient. The reaction isconveniently performed in an aprotic solvent such as tetrahydrofuran,dimethylformamide, hexamethylphosphoramide or dioxan.

The imine of formula (IV) may also suitably be prepared by treatmentwith base of a compound of formula (XII): ##STR23## wherein R¹, R^(x)and Y are as hereinbefore defined and wherein any reactive groups may beprotected and R¹⁸ is a leaving group.

Suitable leaving groups R¹⁸ include trifluoromethanesulphonyl,pentafluorophenylsulphonyl, 4-nitrophenylsulphonyl,2,4-dinitrophenylsulphonyl and nonafluorobentanesulphonyl.

More suitably R¹⁸ is trifluoromethanesulphonyl.

Suitably the base for treatment of a compound of formula (XII) isnon-nucleophilic. Preferably the base is a tri(lower alkyl)amine, suchas for example triethylamine.

Suitable compounds within formula (XII) are those of formula (XIII):##STR24## wherein R¹ and R^(x) are as hereinbefore defined and whereinany reactive groups may be protected; Y3 is: ##STR25## and R¹⁹ is aleaving group.

Suitable leaving groups R¹⁹ include those suitable under R¹⁸.

Other suitable leaving groups R¹⁹ include p-toluenesulphonyl andmethanesulphonyl.

The imine of formula (IV) is also suitably prepared by processes per seknown in the art such as, for example, those disclosed in EuropeanPatent Publication No. 0071395.

The imine of formula (IV) is often an unstable intermediate and isconveniently reacted with the nucleophilic derivative of formamide insitu without isolation of the imine (IV).

It will also be appreciated that the imine (II) may be generated in asimilar manner to that described above from a compound of partialstructure (XIV) or (XV): ##STR26## wherein R¹, R¹⁷ and R¹⁸ are ashereinbefore defined.

The compounds of formulae (XI) and (XIV) may suitably be prepared byprocesses such as, for example, those disclosed in copending U.S. patentapplication Ser. No. 401266 and European Patent Application No.8230382.1 (Publication No. 0071395).

The compounds of formulae (XII), (XIII) and (XV) may be prepared byprocess as described or by processes analogous to those disclosed inEuropean Patent Publication No. 0043546, D. Hagurara et al., J.C.S.Chem.Comm., 1982,578, and P.S.F. Mezes et al., Heterocycles, 1982,19,1207.

The following Examples illustrate the process of the present invention.

EXAMPLE 1 Benzyl 6α-formamido-6β-(phenoxyacetamido)penicillanate

Mercuric acetate (0.160 g, 0.5 mmol) in dry N,N-dimethylformamide (1 ml)was added to a solution of benzyl≢α-(methylthio)-6β-(phenoxyacetamido)penicillanate (0.243 g, 0.5 mmol)and N,N-bis(trimethylsily)formamide, (0.520 g, 2.75 mmol) under argon atroom temperature. The reaction mixture was stirred at room temperaturefor 2 h before being poured into ethyl acetate (30 ml) and washed withwater (6×30 ml), 0.1N hydrochloric acid (30 ml) and brine (30 ml). Theorganic solution was dried over magnesium sulphate, and then evaporatedto afford the crude product. Chromatography on silica gel 60 (<230 meshASTM) eluting with hexane/ethyl acetate 1:1 afforded the title compound(0.160 g, 66%); ν_(max) (CH₂ Cl₂) 3395, 3310, 1792, 1748, 1700, 1690 sh,1495 cm⁻¹ ; δ (CDCl₃) 1.36 (6H,s, 2-CH₃ 's), 4.51 (3H, s, PhOCH₂ and3--H), 5.19 (2H,s, ester CH₂), 5.75 (1H, s, 5--H), 6.70-7.50 (10H, m,aromatics), 8.19 (1H, s, CHO), 8.23 (1H, s, 6β-amido proton) and 8.46(1H, s, --NHCHO).

EXAMPLE 2 Benzyl 6α-formamido-6β-(phenoxyacetamido)penicillanate

Benzyl 6α-(methylthio)-6β-(phenoxyacetamido)penicillanate (0.5 mmol) andN,N-bis(trimethylsily)-formamide (1 mmol) in N,N-dimethylformamide (5ml) were treated with mercuric acetate (0.5 mmol) as described inExample 1. Chromatography afforded the title compound in 65% yield.

EXAMPLE 3 Benzyl 6α-formamido-6β-(phenoxyacetamido)penicillanate

Benzyl 6α-(methylthio)-6β-(phenoxyacetamido)penicillanate (0.5 mmol) andN,N-bis(trimethylsilyl)formamide (1 mmol) in tetrahydrofuran (15 ml)were treated with mercuric acetate (0.5 mmol) as described in Example 1.Chromatography afforded the title compound in 64% yield.

EXAMPLE 4 Benzyl 6α-formamido-6β-(phenoxyacetamido)penicillanate

Cupric acetate monohydrate (0.100 g, 0.5 mmol) was added solid, in oneportion, to a solution of benzyl6α-(methylthio)-6β-(phenoxyacetamido)penicillanate (0.243 g, 0.5 mmol)and N,N-bis(trimethylsilyl)formamide (0.5 ml, 0.443 g, 2.34 mmol) inN,N-dimethylformamide (10 ml). The reaction mixture was stirred at roomtemperature for 2 h before being worked-up and chromatographed asdescribed in Example 1. The title compound was obtained in 26% yield.

EXAMPLE 5 Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-formamidopenicillanate

Mercuric acetate (0.08 g, 0.25 mmol) in dry N,N-dimethylformamide (1 ml)was added to a solution of benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-(methylthio)-penicillanate(0.192 g, 0.25 mmol) and N,N-bis(trimethylsilyl)formamide (0.25 ml, 0.22g, 1.17 mmol) in N,N-dimethylformamide (5 ml) at room temperature. Thereaction mixture was stirred at room temperature under argon for 1 hbefore being poured into ethyl acetate (30 ml) and washed with water(6×30 ml) and brine (30 ml). After drying over magnesium sulphate, theorganic solution was evaporated to afford the crude product, which waschromatographed on silica gel 60 (<230 mesh ASTM) eluting with 5%ethanol in ethyl acetate to give the title compound (0.075 g, 39%);ν_(max) (KBr) 1770, 1740, 1710, 1680 and 1500 cm⁻¹ ; δ(CDCl₃) 0.85 and1.18 (6H, 2s, 2--CH₃ 's), 1.23 (3H, t, J 7 Hz, CH₃ CH₂ N), 2.22 and 2.24(6H, 2s, 2 CH₃ CO), 3.40-3.60 (4H,m, 2CH₂ N), 3.75-3.95 (2H,m, CH₂ N),4.36 (1H, s, 3--H), 5.12 (2H, s, PhCH₂ O), 5.52 (1H, s, 5--H), 5.64 (1H,d, J 7 Hz, NCHCO), 7.12 (1H,d, J 7 Hz, aryl--H), 7.33 (6H, s, phenyl andone aryl-H), 7.45 (1H, d, J 7 Hz, aryl--H), 8.00-8.1 (2H, br s and sharps, 1H on D₂ O exch., NHCHO), 8.79 (1H, br s, D₂ O exch, 6--NH) and 10.11(1H, br d, J 7 Hz, NHCH).

EXAMPLE 6 (a) Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]6α-formamidopenicillanate

Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]6α-(methylthio)penicillanate(0.25 mmol) and N,N-bis(trimethylsilyl)formamide (0.5 mmol) inN,N-dimethylformamide (5 ml) were treated with mercuric acetate (0.25mmol) as described in Example 5, to afford the title compound in 43%yield after chromatography.

(b)6β-[D-2-[(4-Ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)]acetamido-6α-formamidopenicillanicacid, sodium salt

Benzyl6β-[D-2-[(4-Ethyl-2,3-dioxopiperazin-1-yl]-2-(3,4-diacetoxyphenyl)]acetamido-6α-formamidopenicillanate(0.100 g, 0.131 mmole) was dissolved in tetrahydrofuran:water (4:1, 10ml), 10% palladium on charcoal (0.050 g) was added and the mixture washydrogenated at ambient temperature and atmospheric pressure for 1 h.After this time no starting material was visible by t.l.c. The catalystwas filtered off and washed well with water and tetrahydrofuran. To thefiltrate was added 2M sodium 2-ethylhexanoate in methyl isobutyl ketone(0.065 ml) and the solution was evaporated to dryness. Trituration ofthe residue with ether afforded an off-white solid which was filtered,well washed with acetone and ether, then dried to give the titlepenicillin sodium salt (0.060 g, 70%); R_(f) 0.20 in n-butanol:aceticacid:water, 4:1:1, ν_(max) (nujol) 1775, 1710 sh, 1680, 1610, 1500 cm⁻¹; δ(D₂ O) 0.91 and 1.27 (6H, 2s, (CH₃)₂), 1.16 (3H, t, J 7 HZ, CH₃ CH₂N), 2.30 (6H, s, 2 CH₃ CO), 3.30-3.80 (4H, m, 2 CH₂ N), 3.80-4.05 (2H,m, CH₂ N), 4.15 (1H, s, 3--H), 5.46 (1H, s, 5--H, 5.56 (1H, s, NCHCO),7.15-7.55 (3H, m, aryls), 8.07 (1H, s, NHCHO).

MIC (μg/ml) against P.mirabilis 889 is 0.5.

EXAMPLE 7 Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-formamidopenicillanate

Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-(methylthio)penicillanate(0.25 mmol) and N,N-bis(trimethylsilyl)formamide (0.5 mmol) inN,N-dimethylformamide (5 ml) at -20° C. were treated with mercuricacetate (0.5 mmol), and the reaction mixture was stirred at -20° C.under argon for 1 h. Work-up and chromatography as described in Example5, afforded the title compound in 13% yield.

EXAMPLE 8 Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-formamidopenicillanate

Mercuric acetate (0.25 mmol) was added solid, in one portion to asolution of benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-(methylthio)penicillanate(0.25 mmol) and N,N-bis(trimethylsilyl)formamide (0.5 mmol) in drytetrahydrofuran (10 ml) at room temperature. The reaction mixture wasstirred under argon at room temperature for 2 h, before being worked-upand chromatographed as described in Example 5, to afford the titlecompound in 30% yield.

EXAMPLE 9 Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-formamidopenicillanate

Mercuric acetate (0.25 mmol) was added solid, in one portion, to asolution of benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-diacetoxyphenyl)acetamido]-6α-(methylthio)penicillanate(0.25 mmol) and N,N-bis(trimethylsilyl)formamide (0.5 mmol) in drytetrahydrofuran (10 ml) at 0°-5° C. The reaction mixture was stirred at0°-5° C. for 2 h, before being worked-up and chromatographed as inExample 5, to afford the title compound in 38% yield.

EXAMPLE 10 Benzyl6αformamido-6β-(2,2,2-trichloroethoxycarbonylamino)penicillinate

Mercuric acetate (0.296 g, 0.93 mmol) in dry N,N-dimethylformamide (3ml) was added dropwise to a solution of benzyl6α-(methylthio)-6β-(2,2,2-trichloroethoxycarbonylamino)penicillanate(0.497 g, 0.93 mmol) and N,N-bis(trimethylsilyl)formamide (0.4 ml, 1.9mmol) in N,N-dimethylformamide (10 ml) at room temperature. The reactionsolution was stirred at room temperature under argon for 2 h. It wasthen poured into ethyl acetate (50 ml) and washed with water (5×30 ml),1% aqueous sodium sulphide solution (3×30 ml), water (3×30 ml) and brine(30 ml). The organic solution was dried over magnesium sulphate,filtered and evaporated to afford the essentially pure product (0.438 g,88%); ν_(max) (KBr) 3340, 3160, 1790, 1745 and 1670 cm⁻¹ ; δ(CDCl₃) 1.37and 1.53 (6H, 2s, 2--CH₃ 's), 4.52 (1H, s, 3--H), 4.72 (2H, s, Cl₃CCH₂), 5.17 (2H, s, PhCH₂ O), 5.66 (1H, s, 5--H), 6.75 (1H, br s, D₂ Oexch, NH) 7.34 (5H, s, phenyl), 7.70 (1H, brs, D₂ O exch. NHCHO) and8.19 1H, s, NHCHO).

EXAMPLE 11 t-Butyl7α-formamido-7β-(2,2,2-trichloroethoxycarbonylamino)-cephalosporanate

t-Butyl7α-(methylthio)-7β-(2,2,2-trichloroethoxycarbonylamino)cephalosporanate(0.275 g, 0.05 mmol) in dimethylformamide (8 ml) containingN,N-bis(trimethylsilyl)formamide (0.190 g, 1 mmol) was treated withmercuric acetate (0.174 g, 0.55 mmol) in dimethylformamide (2 ml). Thereaction mixture was poured into ethylacetate, washed successively withwater, dilute sodium hydrogen carbonate solution, and brine, dried andevaporated. Chromatography on silica gel afforded the title compound(0.251 g). δ (CDCl₃)1.53 (9H, s, C(CH₃)₃), 2.07 (3H, s, OCOCH₃), 3.28and 3.46 (2H, ABq, J17 Hz, 2--H₂), 4.7-5.3 (5H, m, 6--H, CH₂ OAc, CH₂CCl₃), 6.66 (1H, s, NH), 7.63 (1H, br s, NH), 8.22 (1H, s, CHO);ν_(max).(CH₂ Cl₂), 3380, 1790, 1735, 1700 cm⁻¹.

EXAMPLE 12 (a) Benzyl6-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)penicillanate

Benzyl 6β-(trifluormethanesulphonyl)amino-penicillinate (2.58 g) [D.Hagiwara et al., J.C.S. Chem. Comm., 1982, 578; P.S.F. Mezes et al.,Heterocycles, 19, 1982, 1207] was dissolved in dry dichloromethane (80ml) at 0° C. and 2,2,2-trichloroethylchloroformate (2.5 g) andtriethylamine (893 mg) were added, followed by 4-dimethylaminopyridine(72 mg). The cooling bath was removed. After 2 h the solution was pouredinto ethyl acetate. The solution was washed successively with dilutehydrochloric acid, water, dilute aqueous sodium hydrogen crbonate,brine, dried and evaporated. Chromatography on silica gel afforded thetitle compound (3.27 g). ν_(max) (CHCl₃) 1795, 1785, 1745, 1420, 1130cm⁻¹ ; δ(CDCl₃) 1.42 and 1.67 (6H, 2s (CH₃)₂ C), 4.54 (1H, s, 3--H),4.86 and 4.95 (2H, ABq, J 12 Hz), 5.20 (2H,AA'), 5.5 (1H,d,J4 Hz),5.55(1H,d,J 4 Hz), 7.38(5H, s, aromatics).

(b) Benzyl6β-(2,2,2-trichloroethoxycarbonylamino)-6α-formamidopenicillanate

Benzyl6-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)-penicillanate(613 mg) in dichloromethane (20 ml) was cooled to -5° C. andtriethylamine (150 mg) and bis-(trimethylsilyl)formamide (378 mg;freshly distilled) were added. The cooling bath was removed. After oneand three quarter hours the solution was poured into ethyl acetate andwashed successively with dilute hydrochloric acid, brine, dried andevaporated. Chromatography on silica gel afforded the title compound(441 mg).

EXAMPLE 13 (a) t-Butyl7β-(N-trifluoromethanesulphonylamino)cephalosporanate

t-Butyl 7-aminocephalosporanate (3.28 g) in dichloromethane (100 ml) at-65° C. was treated successively with triethylamine (1.1 g) andtrifluoromethanesulphonic anhydride (3.1 g). After 30 min. at -65° C.,the reaction mixture was washed with dilute hydrochloric acid, followedby brine. The solution was dried and the solvent distilled off in vacuoto give the title compound (4.5 g) ν_(max) (Nujol) 1820, 1735, 1690,1640 cm⁻¹ ; δ(CDCl₃), 1.52 (9H, s, C(CH₃)₃), 2.07 (3H, s, --OCOMe), 3.45(2H, AA', S--CH₂), 4.87 and 5.05 (2H, ABq, J.13 Hz), 4.87 (1H, d, J5Hz), 5.08 (1H d, J5 Hz), 6.5-8.5(1H, very broad s, exch. D₂ O, --NH).

(b) t-Butyl7β-(N-2,2,2-trichloroethoxycarbonyl-N-tri-fluoromethanesulphonylamino)cephalosporanate

t-Butyl 7β-(N-trifluoromethanesulphonylamino)cephalosporanate (920 mg)in dry dichloromethane (30 ml) was treated with triethylamine (222 mg)and 2,2,2-trichloroethylchloroformate (848 mg) for 48 h at roomtemperature. The solution was poured into ethyl acetate, and washedsuccessively with dilute hydrochloric acid, water, dilute aqueous sodiumhydrogen carbonate, and brine. The dried organic layer was evaporatedand chromatographed on silica gel to give the title compound (1.05 g).ν_(max) (CHCl₃) 1795, 1780 sh, 1735 sh, 1720, 1420, 1150 cm⁻¹ ;δ(CDCl₃), 1.53 (9H, s, C(CH₃)₃), 2.08 (3H, s, OCOCH₃), 3.45 (2H, s, CH₂CO--), 4.82 and 5.13 (2H, ABq, J13 Hz), 4.99 (2H, AA' system), 5.08 (1H,d, J5 Hz), and 5.62 (1H, d, J5 Hz).

(c) t-Butyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamidocephalosporanateMethod 1

t-Butyl7β-(N-2,2,2-trichloroethoxylcarbonyl-N-trifluoromethanesulphonylamino)cephalosporanate(63 mg) in dichloromethane (2 ml) was cooled to -40° C. andbis-(trimethylsilyl)formamide (72 mg) added, followed by triethylamine(15 mg). The solution was warmed to -10° C. over 30 min. After a further30 min. at 0/-5° C. the solution was poured into ethyl acetate, washedsuccessively with dilute hydrochloric acid and brine, dried andevaporated. Chromatography on silica gel gave the title compound (30mg), containing ca 5% of delta-2 isomer.

Method 2

t-Butyl7β-(N-2,2,2-trichlorethoxycarbonyl-N-trifluoromethanesulphonylamino)cephalosporanate(63 mg) in dichloromethane (2 ml) was treated withbis-(trimethylsilyl)formamide (76 mg) and triethylamine (11 mg). After16 h at room temperature the solution was worked up as in Method 1.Chromatography on silica gel afforded the product (48 mg) whichconsisted of the title compound (20%) and t-butyl 3-acetoxymethyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamidoceph-2-em-4-carboxylate(80%). The latter showed inter alia δ(CDCl₃) 1.45 (9H, s, C(CH₃)₃), 2.08(3H, s, --OCOCH₃), 4.92 (1H, slightly broadened s, 4--H), 5.42 (1H, s,6--H), 6.3 (1H, slightly broadened s, 2--H).

The mixture of Δ-2 and Δ-3 isomers (48 mg) was dissolved in ethylacetate(2 ml) at -10° C. and m-chloroperbenzoic acid (16 mg) added. After 15min. the solution was washed with dilute aqueous sodium hydrogencarbonate and brine, dried and evaporated. The residue was dissolved inmethanol. After 30 min. the solvent was evaporated off and the residuedried in vauco. The product was dissolved in dichloromethane (2 ml) at0° C. and phosphorus trichloride (36 mg) added. After 45 min thesolution was poured into ethyl acetate and washed successively withdilute aqueous sodium hydrogen carbonate and brine. The organic layerwas dried and evaporated. Chromatography on silica gel afforded t-butyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamidocephalosporanate (25mg).

Method 3

t-Butyl7β-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)cephalosporanate(63 mg) in dichloromethane (2 ml) at -60° C. was treated withbis-(trimethylsilyl)formamide (76 mg) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (20 mg). The temperature wasallowed to reach -5° C. After 30 min at this temperature the reactionmixture was worked up as in Method 1. Chromatography on silica gel gavethe product which contained some of the title compound, but was mainlyt-butyl3-acetoxymethyl-7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamido-ceph-2-em-4-carboxylate.The latter was converted into the title compound by theoxidation/reduction sequence described in Method 2 of this example.

EXAMPLE 14 (a) t-Butyl7β-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)cephalosporanate-1α-oxide

t-Butyl7β-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)cephalosporanate(648 νmg) was dissolved in ethyl acetate (20 ml) at -10° C. andm-chloroperbenzoic (193 mg; 90% pure) added. The solution was washedwith dilute aqueous sodium hydrogen carbonate, brine, dried andevaporated. Chromatography on silica afforded the title compound (466mg). ν_(max) (CHCl₃) 1810, 1750, 1730, 1425, 1150, 1035 cm⁻¹ ; δ(CDCl₃)1.53 (9H, s, C(CH₃)₃), 2.08 (3H, s, --OCOCH₃), 3.48 and 3.99 (2H, ABq, J16 Hz, SCH₂ ), 4.6 (1H, d, J5 Hz), 4.84 and 5.19 (2H, ABq, J 14 Hz),4.91 (2H, AA'), 5.87 (1H, d, J 5 Hz).

(b) t-Butyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamidocephalosporanate-1α-oxide

t-Butyl7β-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)cephalosporanate-1α-oxide(64 mg) in dichloromethane (2 ml) was treated withbis-(trimethylsilyl)formamide (72 mg) and triethylamine (10 mg). After10 min. the solution was diluted with ethyl acetate, washed successivelywith dilute hydrochloric acid, water, dilute aqueous sodium hydrogencarbonate and brine, dried and evaporated. Chromatography on silica gelgave the title compound (15 mg). ν_(max) (CHCl₃) 3480, 3200br, 1805,1730, 1700 sh, 1040 cm⁻¹ ; δCDCl₃) 1.6 (9H,s,C(CH₃)₃), 2.13 (3H,s,OCOCH₃), 3.47 and 4.0 (2H, ABq, J 16 Hz, SOCH₂), 4..67 (2H, AA'),4.5-5.1 (3H, m), 7.4 (1H, bs, exch. D₂ O) 8.07 (2H, s, 1H exch. D₂ O).

Reduction of this material as described in Example 13(c) (Method 2) gavet-butyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamidocephalosporanate.

EXAMPLE 15 t-Butyl7β-(t-butoxycarbonylamino)7α-formamidocephalosporanate

t-Butoxycarbonyl azide (312 mg) was dissolved in dichloromethane (10 ml)and triphenylphosphine (573 mg) added cautiously in dichloromethane (10ml). After 10 min. t-butyl 7-oxocephalosporanate (715 mg) (D. Hagiwaraet al., J.C.S. Chem. Comm., 1982, 578) was added, followed by furthert-butyl 7-oxocephalosporanate (82 mg) after 2 h. After a further 2 h.bis-(trimethylsilyl)formamide (826 mg) was added.

After 1 h the reaction mixture was diluted with ethyl acetate and washedwith water. The organic layer was separated, washed with dilutehydrochloric acid, brine, dried and evaporated. Chromatography on silicagel gave the title compound (650 mg). ν_(max) (CHCl₃) 3420, 1790, 1720br cm⁻¹ ; δ(CDCl₃) 1.47 (9H, s, C(CH)₃)₃), 1.53 (9H, s, C(CH₃)₃), 2.05(2H, s, OCOCH₃), 3.22 and 3.5 (2H, ABq, J 17 Hz, SCH₂), 4.72 and 5.06(2H, ABq, J 14 Hz, --CH₂ OCO--), 5.15 (1H, s, 6--H), 5.91 (1H, slightlybroadened s, exch. D₂ O,NH), 7.42 (bs, 1H, exch. D₂ O), 8.21 (s, 1H,CHO).

EXAMPLE 16 (a) Benzyl6-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)penicillanate-1α-oxide

Benzyl6-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)penicillanate(613 mg) was dissolved in dry dichloromethane (10 ml) at -10° C. andperacetic acid (1.5 ml of 5.24% solution in acetic acid) was added.After 16 hour at 0° C. the solvent was evaporated in vacuo. Afteraddition of toluene and repetition of the evaporation (three times), theresidue was chromatographed on silica gel to give the title compound(516 mg). ν_(max) (CHCl₃) 1810, 1755, 1425, 1130 cm⁻¹ ; δ(CDCl₃) 1.18and 1.68 (6H,2s, (CH₃)₂ C), 4.45 (1H,s,3--H), 4.73 (1H,d,J 4.5 Hz), 4.81and 4.97 (2H,ABq, J 12 Hz), 5.21(2H,AA'), 5.7 (1H,d,J 4.5 Hz), 7.35(5H,s, aromatics).

(b) Benzyl 6β-(2,2,2-trichloroethoxycarbonylamino)-6α-formamidopenicillanate-1α-oxide

Benzyl6-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)penicillanate-1α-oxide(63 mg) was dissolved in dry dichloromethane (2 ml) at -10° C. andbis-(trimethylsilyl)formamide (40 mg) was added, followed immediately bytriethylamine (10 mg). The temperature was allowed to rise to -5° C. andafter 40 minutes the solution was poured into ethyl acetate and washedsuccessively with dilute hydrochloric acid, brine, dried and evaporated.Chromatography on silica gel afforded the title compound (41 mg);ν_(max) (CHCl₃) 3200 (broad), 1800, 1740, 1700 cm⁻¹ ; δ(CDCl₃) 1.25 and1.48 (6H, 2s, (CH₃)₂ C), 4.56(1H,s,3--H), 4.68 and 4.89 (2H, ABq, J13Hz), 5.16 (1H,s,), 5.2 (2H,AA') 7.2b(1H,s,exch.D₂ O) 7.33 (5H,s,aromatics), 8.03b(1H,s, exchD₂ O), 8.17 (1H,s, CHO).

EXAMPLE 17 (a) Benzyl6β-(trifluoromethanesulphonyl)aminopenicillanate-1β-oxide

Benzyl 6β-(trifluoromethanesulphonyl)aminopenicillanate (3.12 g) wasdissolved in dry dichloromethane (50 ml) at -10° C. and peracetic acid(1 ml of 52.4% solution in acetic acid) added. After 15 minutes thesolvent was evaporated. After addition of toluene and repetition of theevaporation (three times), the residue was chromatographed on silica gelto give the title compound (2.6 g); ν_(max) (CHCl₃) 3250, 1810, 1750,1440, 1140 cm⁻¹ ; δ(CDCl₃) 1.05 and 1.64(6H,2s,(CH₃)₂ C), 4.69(1H,s,3H),4.98(1H,d,J 4.5 Hz), 5.1 and 5.28(2H,ABq,J12 Hz), 5.31 (1H,d,J 4.5 Hz),7.34 (5H,s,aromatics). Triflate NH too broad to observe.

(b) Benzyl6-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)penicillanate-1β-oxide

Benzyl 6β-(trifluoromethanesulphonyl) aminopenicillanate-1β-oxide (988mg) was dissolved in dry dichloromethane (30 ml) at -10° C. andtrichloroethylchloroformate (844 mg) added, followed by pyridine (240mg). The temperature was raised to 0° C. and after 11/2 hour thereaction mixture was poured into ethyl acetate/dilute hydrochloric acid.The organic layer was separated, washed with brine, dried andevaporated. Chromatography on silica gel gave the title compound (1.14g); ν_(max) (CHCl₃) 1750, 1420, 1125, 1045 cm⁻¹ ; δ(CDCl₃) 1.05 and 1.6(6H, 2s, (CH₃)₂ C), 4.7 (1H,s,3--H), 4.88(2H,AA'), 5.01(1H,d,J5 Hz) 5.13and 5.3(2H,ABq,J12 Hz), 5.52 (1H,s,J5 Hz), 7.34(5H,s,aromatics).

(c) Benzyl 6β-(2,2,2-trichloroethoxycarbonylamino)6α-formamidopenicillanate-1β-oxide

Benzyl6-(N-2,2,2-trichloroethoxycarbonyl-N-trifluoromethanesulphonylamino)penicillanate-1β-oxide(126 mg) was dissolved in dry dichloromethane (3 ml) at -10° C. andbis-(trimethylsilyl)formamide (80 mg) was added, followed immediately bytriethylamine (20 mg). After 20 min at -10° C./-5° C. the solution waspoured into ethyl acetate, and washed with dilute hydrochloric acid,followed by brine, dried and evaporated. Chromatography on silica gelafforded the title compound (81 mg); ν_(max) (CHCl₃) 3400, 3250, 1795,1735(broad), 1700, 1050 cm⁻¹ ; δ(CDCl₃) 1.06 and 1.6 (6H,2s, (CH₃)₂C)4.68(1H,s,3--H), 4.72 (2H,AA'), 5.2(1H,s), 5.13 and 5.32(2H,ABq,J12Hz), 7.35(5H,s,aromatics), 7.45b (1H,s,exch. D₂ O), 8.22(1H,s,CHO). OneNH obscured by other peaks.

EXAMPLE 18 (a) t-Butyl 7β-(N-pentafluorophenylsulphonylamino)cephalosporanate

t-Butyl 7-aminocephalosporanate (371 mg) was dissolved in drydichloromethane (4 ml) at -20° C. and pentafluorophenylsulphonylchloride (305 mg) added, followed by pyridine (86 mg). After 30 minutesthe cooling-bath was removed and the solution left at room temperaturefor 21 hour. The solution was diluted with ethyl acetate and washedsuccessively with dilute hydrochloric acid, aqueous sodium hydrogencarbonate and brine, dried and evaporated. Chromatography on silica geleluting with ethyl acetate-dichloromethane mixtures gave the titlecompound (332 mg); m.p. 204°-205° C. (ethyl acetate-hexane); ν_(max)(Nujol) 3100, 1810, 1730, 1700, 1640, 1460, 1160, 980 cm⁻¹ ; δ(CDCl₃)1.48 (9H,s,C(Me)₃)2.03 (3H,s,OCOCH₃), 3.3 and 3.57 (2H,ABq,J18 Hz,S--CH₂), 4.75 and 5.09 (2H, ABq,J14 Hz,CH₂ OCO), 4.93 (1H,d,J5 Hz),5.4(1H, slightly broadened, d,J5 Hz, 7--H), 6.4b(1H,s,exch D₂ O).(Found: C,43.1; H, 3.7; N,4.7; S 11.3 C₂₀ H₁₉ N₂ O₇ S₂ F₅ requiresC,43.0; H,3.4; N,5.0; S,11.5%).

(b) Butyl7β-(N-pentafluororphenylsulphonyl-N-2,2,2-trichloroethoxycarbonylamino)cephalosporanate

t-Butyl 7β-(N-pentafluorophenylsulphonylamino) cephalosporanate (246 mg)was dissolved in dichloromethane (10 ml) at -20° C. andtrichloroethylchloroformate (186 mg) added followed by pyridine (52 mg).The solution was diluted with dichloromethane, washed with dilutehydrochloric acid followed by brine, dried and evaporated.Chromatography on silica gel gave the title compound (320 mg) as a whitesolid after trituration with ether hexane; ν_(max) (CHCl₃) 1790,1730(broad), 1735, 1500 1160, 990 cm⁻¹ ; δ(CDCl₃) 1.53 (9H,s,(CH₃)₃),2.04(2H,s,OCOCH₃), 3.42(2H,AA'), 4.77(2H,AA') 4.77 and5.05(2H,ABq,J13 Hz), 5.08 (1H,d,J5 Hz), 5.96(1H,d,J5 Hz).

(c) t-Butyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamidocephalosporanate

t-Butyl7β-(N-pentafluorophenylsulphonyl-N-2,2,2-trichloroethyoxycarbonylamino)cephalosporanate(63 mg) was dissolved in dry dichloromethane at -10° C. andbis-(trimethylsilyl)formamide (37 mg) was added, followed immediately bytriethylamine (15 mg). The cooling-bath was removed and the solutionkept at room temperature for 2 hour. The solvent was evaporated and theresidue chromatographed on silica gel to give a mixture (12 mg) of thetitle compound (15%) and t-butyl3-acetoxymethyl-7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamido-ceph-2-em-4-carboxylate(85%).

EXAMPLE 19 (a) t-Butyl 7β-(N-2,4-dinitrophenylsulphonyl)aminocephalosporanate

t-butyl 7-aminocephalosporanate (742 mg) dissolved in drydichloromethane (15 ml) at -10° C. was treated with pyridine (173 mg)and 2,4-dinitrophenylsulphonyl chloride (588 mg). The cooling-bath wasremoved. The solution stirred at room temperature for 16 h, then pouredinto ethyl acetate, and washed successively with dilute hydrochloricacid, brine, dilute aqueous sodium hydrogen carbonate, brine (×2), driedand evaporated. Chromatography of the residue on silica gel eluting withethyl acetate-dichloromethane mixtures gave the title compound (588 mg);ν_(max) (Nujol) 3225, 3090, 1795, 1730, 1710, 1738, 1535, 1450, 1365,1170 cm⁻¹ ; δ(CDCl₃ 30 [CD₃ ]₂ SO) 1.49 (9H,s,(CH ₃)₃ C), 2.02 (3H, s,OCOCH₃), 3.12 and 3.48 (2H, ABq, J 18 Hz), 4.72 and 5.03 (2H, ABq, J 13Hz, 4.96 (1H, d, J 4.5 Hz) 5.38 (1H, d, J 4.5 Hz), 8.4-8.65 (3H, m,aromatics). SO₂ NH is very broad and not clearly visible.

(b) t-butyl7β-(N-2,4-dinitrophenylsulphonyl-N-2,2,2-trichloroethoxycarbonylamino)cephalosporanate

t-Butyl 7β-(N-2,4-dinitrophenylsulphonylamino) cephalosporanate (279 mg)in dry dichloromethane (10 ml) at -5° C. was treated withtrichloroethylchloroformate (211 mg) and pyridine (44 mg). The solutionwas diluted with ethylacetate, washed with dilute hydrochloric acid,followed by brine, dried and evaporated. Chromatography on silica gelgave the title compound. ν_(max) (CHCl₃) 1790, 1738, 1730, 1545, 1345,1170, 1150 cm⁻¹ ; δ(CDCl₃) 1.55 (9H, s, (CH₃)₂ C), 2.09 (3H, s, OCOCH₃),3.40 and 3.57 (2H, ABq, J 17.9 Hz), 4.72 and 4.81 (2H, ABq, J 11.8 Hz),4.80 and 4.99 (2H, ABq, J 13 Hz), 5.2 (1H, d, J 5.1 Hz), 5.99 (1H, d, J5.1 Hz) 8.59-8.76 (3H, m, aromatics).

(c) t-Butyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamidocephalosporanate

t-Butyl7β-(N-2,4-dinitrophenylsulphonyl-N-2,2,2-trichloroethoxycarbonylamino)cephalosporanate(122 mg) in dry dichloromethane (3 ml) at -10° C. was treated withbis-trimethylsilyformamide (96 mg) and triethylamine (25 mg). Thecooling bath was removed and the solution stirred at room temperaturefor 41/2 h. Ethyl acetate was added and the solution washed with dilutehydrochloric acid, followed by brine, dried and evaporated.Chromatography on silica gel gave a mixture (37 mg) of the titlecompound (40%) and t-butyl3-acetoxymethyl-7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamido-ceph-2-em-4-carboxylate(60%).

EXAMPLE 20 Benzyl 6α-formamido-6β-(phenylacetamido)penicillanate

(a) A solution of benzyl6α-methylsulphinyl-6β-(phenylacetamido)-penicillanate (52 mg, 0.107mmol) in dry dichloromethane (5 ml) and bis-(trimethylsilyl)formamide(40.4 mg, 0.214 mmol) was treated with triethylamine (11.9 mg, 0.118mmol, 16.4 μl) for 19 h at room temperature. The mixture was thendiluted with dichloromethane (15 ml) and washed successively with diluteaqueous hydrochloric acid, dilute aqueous sodium hydrogen carbonate andsaturated brine. The solution was then dried (MgSO₄) and evaporated toafford the title compound (24 mg, 48%); (see UK Patent Application, No.GB2107307A).

(b) A solution of benzyl6α-methylsulphinyl-6β-(phenylacetamido)penicillanate (70 mg, 0.144 mmol)in dry tetrahydrofuran (10 ml) and bis-(trimethylsilyl)-formamide (54.4mg, 0.288 mmol) was heated under reflux for 3.5 h and then allowed tostand at room temperature for 18 h. The solvent was then evaporated invacuo and the residue taken up in ethyl acetate (20 ml). The solutionwas washed successively with 2N-hydrochloric acid (15 ml), saturatedaqueous sodium hydrogen carbonate (10 ml) and saturated brine (10 ml),dried (MgSO₄) and evaporated. The yellow gum so obtained waschromatographed on silica gel to give the title compound (61 mg, 91%).

EXAMPLE 21 Benzyl6α-formamido-6β-(phenylacetamido)penicillanate-1β-oxide

A solution of benzyl6α-methylsulphinyl-6β-(phenylacetamido)penicillanate-1β-oxide (80 mg,0.159 mmol) in dry tetrahydrofuran (5 ml) andbis-(trimethylsilyl)formamide (120 mg, 0.635 mmol) was heated underreflux for 6 h and then allowed to stand at room temperature for 18 h.The solvent was then evaporated in vacuo and the residue taken up inethyl acetate (15 ml). The solution was washed successively with2N-hydrochloric acid (10 ml) and saturated brine (10 ml), dried (MgSO₄)and evaporated. Chromatography of the crude product on silica gel gavethe title compound (30 mg, 39%) ν_(max) (CHCl₃) 3250, 2930, 1795, 1745,and 1680 cm⁻¹, δ(CDCl₃) 1.01 and 1.56 (3H,s), 3.53 (2H,s), 4.72 (1H,s),5.08 (1H,s), 5.24 (2H, ABq, J 12 Hz), 7.26 (5H,s), 7.37 (5H,s), 7.78(1H, br s), 7.90 br (1H, s) and 7.99 and 8.33 (together 1H each s),(addition of D₂ O caused the signals at 7.78 and 7.90 to disappear).

EXAMPLE 22 Benzyl6α-formamido-6β-[D-2-phenyl-2-(2,2,2-trichloroethoxycarbonylamino)acetamido]penicillanate

Benzyl6α-methylthio-6β-[D-2-phenyl-2-(2,2,2-trichloroethoxycarbonylamino)acetamido]penicillanate(3.30 g, 5 mmol) and N,N-bis(trimethylsilyl)formamide (2.2 ml, 10 mmol)in N,N-dimethylformamide (30 ml) was treated with silver acetate (0.840g, 5 mmol) and stirred at room temperature for 0.5 h. The reactionmixture was diluted with ethyl acetate and water and then filteredthrough Celite. The two phases of the filtrate was separated and theethyl acetate layer was washed with water and brine before being driedover magnesium sulphate. The solution was filtered and evaporated todryness to yield the crude product as a white foam (3.23 g). This waschromatographed on silica gel 60 (<230 mesh ASTM) (120 g) eluting with2:1 hexane/ethyl acetate grading to 1:1 hexane/ethyl acetate to yieldthe title compound as a white foam (1.70 g, 2.6 mmol, 52% yield);ν_(max) (CH₂ Cl₂) 3500 sh, 3410, 3300, 1790, 1745, 1695, 1495, 1205 cm⁻¹; δ(CDCl₃) 0.98 and 1.28 (6H, 2s, C(CH₃)₂), 4.38 (1H,s, 3--H), 4.57,4.73 (2H, ABq, J 13 Hz, CH₂ CCl₃), 5.13 (2H,s, CH₂ Ph), 5.45-5.72 (2H,m, NHCHCO, 5--H), 6.82 (1H, d, J 7 Hz, NHCH), 7.10-7.62 (10H, m,aromatics), 7.88 (1H, s, NH), 8.09 (1H, s, NHCHO), and 8.55 (1H, s, NH).(Found: MH⁺, 657. C₂₇ H₂₇ Cl₃ N₄ O₇ S requires M, 656).

EXAMPLE 23 Benzyl6β-[D-2-[(4-n-butyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-6α-formamidopenicillanate

Benzyl 6β-[D-2-[(4-n-butyl-2,3-dioxopiperazin-1-yl)carbonyl-amino]-2-phenylacetamido]-6α-(methylthio)penicilllanate (400mg; 0.59 mMole) in tetrahydrofuran (5 ml) was treated at roomtemperature with mercuric acetate (187 mg; 0.59 mMole) thenN,N-bis-(trimethylsilyl)formamide (218 mg; 1.2 mMole). It was stirred atroom temperature for 0.5 h, diluted with ethyl acetate (25 ml) andfiltered through Dicalite. The filtrate was washed with water (25 ml),saturated brine (25 ml), dried over anhydrous magnesium suphate andevaporated to dryness in vacuo to yield a yellow foam. Chromatography onsilica gel 60(<230 mesh ASTM), eluting with 50% ethyl acetate incyclohexane, gave the title compound (76 mg; 19% yield) as a white foam,ν_(max) (tetrahydrofuran) 1785, 1740, and 1693 cm⁻ ; δ[CD₃)₂ CO] 0.92and 1.16 (6H, 2s, 2-C(CH₃)₂ ), 0.93 (3H, t, J8 Hz, (CH₂)₂ CH₃),1.24-1.45 and 1.52-1.69 (4H, 2m, NCH₂ (CH₂)₂ CH₃), 3.40-3.53, 3.62-3.74and 3.95-4.08 (6H, 3m, N(CH₂)₂ NCH₂), 4.39 (1H, s, 3--H), 5.12-5.28 (2H,m, CH₂ Ph), 5.58 (1H, s, 5--H), 5.62-5.73 (1H, m, CHCO), 7.25-7.63 (10H,2m, aromatics), 8.18 (1H, d, J2 Hz, CHO), 8.23 (1H, brs, NHCHO), 8.77(1H, brs, CONH), 10.04 (1H, d, J7 Hz, NHCHCO).

EXAMPLE 24 (a) Benzyl6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)-carbonylamino]-2-[4-(benzyloxycarbonyloxy)phenyl]acetamido]-6α-formamidopenicillanate

A solution of benzyl6α-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-[4-benzyloxycarbonyloxy)phenyl]acetamido]-6α(methylthio) penicillanate (2.01 g, 2.5mmol) and N,N-bis(trimethylsilyl)formamide (0.95 g, 5 mmol) inN,N-dimethylformamide (30 ml) under argon, was treated with a solutionof mercuric acetate (0.80 g, 2.5 mmol) in N,N-dimethylformamide over 10minutes. The resulting solution was stirred at room temperature for 4 h,before being poured into ethyl acetate (150 ml) and washed with water(5×100 ml) and brine (50 ml). The organic solution was dried overmagnesium sulphate and then evaporated to dryness to leave a pale yellowglass. This was purified by chromatography on silica gel 60 eluting withethyl acetate grading to 5% ethanol/ethyl acetate, to afford the titlecompound 1.17 g, 59%). ν_(max) (CH₂ Cl₂) 3275, 1790, 1770, 1750, 1725,1715, 1695, 1682 sh, 1500, 1210 cm⁻¹ ; δ[(CD₃)₂ CO] 0.97 and 1.18 (6H,2s, gem dimethyls), 1.17 (3H, t, J7 Hz, CH₂ CH₃), 3.48 (2H, q, J7 Hz,CH₂ CH₃), 3.65 (2H, m, piperazine CH₂), 4.00 (2H, m, piperazine CH₂),4.39 (1H, s, 3--H), 5.18 (2H, s, ester CH₂), 5.26 (2H, s, carbonate CH₂)5.58 (1H, s, 5--H), 5.73 (1H, d, J7 Hz, collapses to singlet on D₂ Oexchange, α-proton), 7.10-7.70 (14H, m, aromatics), 8.16 (1H, s, NHCHO),8.23 (1H, s, exchangeable with D₂ O, NHCHO), 8.88 (1H, d, exchangeablewith D₂ O, 6β-amido proton), and 10.05 (1H, s, J7 Hz, exchangeable withD₂ O α-amido proton).

(b) 6β-[D-2-[(4-Ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(4-hydroxyphenyl) acetamido]-6α-formamidopenicillanicacid, sodium salt

A solution of benzyl6β-[(D-2-[4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-[4-(benzyloxycarbonyloxy)phenyl]acetamido]-6α-formamidopenicillanate(0.50 g, 0.625 mmol) in tetrahydrofuran (15 ml) was added to asuspension of 10% palladium on charcoal (0.50 g) in ethanol (15 ml) andwater (1 ml) which had been pre-hydrogenerated for 0.5 h. The mixturewas then hydrogenated for 45 minutes, and the catalyst was filtered andwashed with dilute sodium bicarbonate solution. The filtrate was thenwashed with ethyl acetate, saturated with sodium chloride and acidifiedto pH 1.5 before extraction of the product into tetrahydrofuran/ethylacetate (50:50). The combined extracts were washed with brine, driedover magnesium sulphate and evaporated to leave the free acid as a whitesolid (0.25 g). This was suspended in water and the pH carefullyadjusted from 2.0 to 7.0 by addition of dilute sodium bicarbonatesolution. The resulting solution was filtered and freeze dried to affordthe title penicillin (256 mg, 69%). Hplc showed one major peak, ν_(max)(KBr) 1770, 1710, 1685, 1670, 1610, 1510 cm⁻¹ δ(D₂ O) 0.95 and 1.33 (6H,2s, gem dimethyls), 1.21 (3H, t, J7 Hz CH₂ CH₃) 3.50 (2H, q, J7 Hz, CH₂CH₃), 3.65 (2H, m, piperazine CH₂), 3.98 (2H, m, piperazine CH₂) 4.16(1H, s, 3--H) 5.37 (1H, s, 5--H) 5.59 (1H, s, α-proton), 6.86 and 7.35(4H, AA'BB', J9 Hz, aromatics) and 8.00 (1H, s, NHCHO). MIC againstP.mirabilis 889 is 0.1 μg/ml.

EXAMPLE 25 Benzyl 6β-(phenoxyacetamido)-6α-formamidopenicillanate

Benzyl 6β-(phenoxyacetamido)-6α-(methylthio) penicillanate (0.49 g, 1mmol) was dissolved in dry dimethylformamide (8 ml) and cooled to -40°C. under argon with stirring. Silver (I) acetate (0.25 g, 1.5 mmol) wasadded, following by N-hydroxysuccinimide (0.17 g, 1.5 mmol). Stirringwas continued while the mixture regained room temperature. After 1.5 hthe mixture was partitioned between ethyl acetate (40 ml) and water (40ml). The organic phase was separated and washed further with water (4×40ml), then with brine, dried over anhydrous magnesium sulphate andevaporated to give a foam. Without further purification, this materialwas redissolved in dry tetrahydrofuran (5 ml), cooled to 0° C. andstirred under argon. Bis(trimethylsilyl)formamide (0.48 ml, 2.5 mmol)was then added, followed quickly by triethylamine (0.28 ml, 2 mmol). Theresulting solution was allowed to regain room temperature, and after 1 hwas partitioned between ethyl acetate (20 ml) and 0.5 M hydrochloricacid (2×20 ml). The organic solution was washed further with saturatedaqueous sodium hydrogen carbonate (2×20 ml), water and brine, then driedover anhydrous magnesium sulphate. Evaporation gave crude product (0.47g), which was chromatographed on silica gel (230-400 mesh, 50 g),eluting with 5% methanol in chloroform. Appropriate fractions werecombined and evaporated to afford the 6α-formamidopenicillin (0.38 g,78%), R_(f) 0.4 in 10% methanol-chloroform; ν_(max) (KBr), 1787, 1744,1688, 1599, 1589 and 1492 cm⁻¹ ; δ(CDCl₃) 1.35; 1.37 (6H, 2s, 2--CH₃'s), 4.51 (1H, s, 3--H), 4.52 (2H, s, OCH₃ CO), 5.19 (2H, ABq, ArCH₂ O)5.73 (1H, s, 5--H), 6.9-7.1 (3H, m, ArH), 7.2-7.5 (8H, m, ArH+NH), 8.01(1H, br, s, D₂ O exchanged, NHCHO) 8.21 (1H, v narrowed, s on D₂ Oexchange, NHCHO).

EXAMPLE 26 Benzyl6β-[D-2-[(4-Ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-6α-formamidopenicillanate

Benzyl6β-(D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-6α-(methylthio)penicillate(1.63 g, 2.5 mmol) was dissolved in dry dimethylformamide (40 ml). Thesolution at room temperature was stirred under argon. Mercury (II)acetate (0.80 g, 2.5 mmol) was added in one portion, followed rapidly bybis(trimethylsilyl)formamide (0.95 ml, 5 mmol). After 1 h the reactionmixture, which showed no starting material by t.l.c., was partitionedbetween ethyl acetate (150 ml) and water (100 ml). The organic phase wasseparated and washed further with water (4×100 ml) and brine (50 ml),then dried over anhydrous magnesium sulphate. Evaporation gave crudeproduct (1.48 g), which was subjected to chromatography on silica gel(230-400 mesh, 148 g) eluting with 2.5% methanol in chloroform.Appropriate fractions were pooled and evaporated to give the title6α-formamidopenicillin (0.95 g, 59%); R_(f) 0.31 in 10%methanol-chloroform; ν_(max) (KBr) 1785, 1740 sh, 1715, 1685, and 1500cm⁻¹ ; δ[(CD₃)₂ CO] 1.13, 1.23, (6H, 2s, 2--CH₃ 's), 1.13 (3H, t, NCH₂CH₃), 3.3-3.75 (4H, m, 2 NCH₂ 's) 3.97 (2H, m, NCH₂), 4.33 (1H, s,3--H), 5.13 (2H, s, ArCH₂ O), 5.20 L (1H, s, 5--H), 5.57 (1H, d, CHN),7.1-7.6 (10H, m, ArH), 8.12 (1H, s, NHCHO). The NH signals were alreadyappreciably broadened by exchange with solvent H₂ O; on D₂ O exchangethe δ5.57 signal became a singlet and the δ8.12 signal sharpened.

EXAMPLE 27 (a) Benzyl 6β-(Nonafluorobutanesulphonylamino)penicillanate

Benzyl 6-aminopenicillanate (ex. benzyl 6-aminopenicillanate, p-toluenesulphonic acid salt (466 mg; 0.97 mmol)) was dissolved in anhydrous MDC(5 ml), cooled to -60° under argon and triethylamine (109 mg; 1.06 mmol)added, followed by nonafluorobutanesulphonic acid anhydride (624 mg;1.06 mmol). The reaction mixture was allowed to warm to 0° over 1 h,diluted with ethyl acetate and washed with dilute hydrochloric acid,saturated sodium hydrogencarbonate solution, brine, dried (MgSO₄) andevaporated. Chromatography of the residue gave two products, benzyl6β-(N,N-bis-nonfluorobutanesulphonylamino)penicillanate (54 mg; 6%).ν_(max) (CHCl₃) 1795, 1750, 1390, 1140 cm⁻¹ ; δppm (CDCl₃) 1.44 (3H,s),1.63 (3H,s), 4.52 (1H,s), 5.20 (2H,s), 5.26 (1H,d,J 4.2 Hz), 5.58(1H,d,J 4.2 Hz), 7.37 (5H,s) and the title product (130 mg; 23%) ν_(max)(CHCl₃) 3345, 1795, 1745, 1390, 1140 cm⁻¹ ; δppm (CDCl₃) 1.44 (3H,s),1.63 (3H,s), 4.52 (1H,s), 5.20 (2 H,s), 5.26 (1H,d,J 4.2 Hz), 5.58(1H,d,J 4.2 Hz), 7.38 (5 H,s). (Found: M⁺, 588.0441, C₁₉ H₁₇ N₂ O₅ S₂ F₉requires M 588.0436).

(b) Benzyl6β-(N-2,2,2-trichloroethoxycarbonyl-N-nonafluorobutanesulphonyl-amino)-penicillanate

Benzyl 6β-(nonafluorobutanesulphonylamino)penicillanate (169 mg; 0.287mmol) was dissolved in dry MDC (5 ml), cooled to 0° C. andtrichloroethylchloroformate (121 mg; 0.594 mmol), triethylamine (44 mg;0.43 mmol), and 2-N,N-dimethylaminopyridine (3.5 mg; 0.029 mmol) addedsuccessively. The reaction mixture was removed from the cooling bath,stirred for 2 h, and poured into ethyl acetate. The organic phase waswashed with dilute hydrochloric acid, dilute sodium hydrogencarbonate,brine, dried (MgSO₄) and evaporated. Chromatography on silica gelafforded the title product (121 mg: 55%) ν_(max) (CHCl₃) 1798, 1978,1740, 1350, 1140 cm⁻¹ ; δppm (CDCl₃) inter alia 1.43 (3H,s), 1.69(3H,s), 4.57 (1H,s), 4,85 and 4.95 (2H, ABq, J 11.7 Hz), 5.19 (2H, AA'),5.54 (2H,s), 7.38 (5H,s).

Benzyl 6α-formamido-6β-(2,2,2-trichloroethoxycarbonylamino)penicillanate

Benzyl6β-(N-2,2,2-trichloroethyoxycarbonyl-N-nonafluorobutanesulphonyl-amino)-penicillanate(100 mg; 0.13 mmol) was dissolved in dry MDC (3 ml), cooled to -5° C.and treated sequentially with bis-(trimethylsilyl)formamide (56 μl; 0.26mmol) and triethylamine (27 μl; 0.20 mmol). After removing the coolingbath, the reaction was allowed to warm towards room temperature over 2h. The reaction mixture was poured into ethyl aceate, washed with verydilute hydrochloric acid, brine, dried (MgSO₄) and evaporated.Chromatography on silica gel afforded the title product (47 mg; 68%)identical to authentic material.

EXAMPLE 28 (a) t-Butyl7β-(Nonafluorobutanesulphonylamino)cephalosporanate

t-Butyl 7-amino cephalosporanate (328 mg; 1.0 mmol) was dissolved in dryMDC (5 ml), cooled to -60° C. under argon and triethylamine (109 mg; 1.1mmol) added, followed by nonafluorobutanesulphonic acid anhydride (624mg; 1.1 mmol). The reaction was allowed to warm towards 0° C. over 1 h,poured into ethyl acetate, washed with dilute hydrochloric acid,saturated sodium hydrogencarbonate, brine, dried (MgSO₄) and evaporated.The residue was chromatographed on silica gel to afford the titleproduct (351 mg; 58%) ν_(max) (Nujol) 1815, 1738, 1695, 1645, 1350, 1145cm⁻¹ ; δppm (CDCl₃) 1.53 (9H,s), 2.09 (3H,s), 3.44 and 3.59 (2H, ABq, J18.5 Hz), 4.82 and 5.16 L (2H, ABq, 13.5 Hz), 4.97 (1H, d, J 4.9 Hz),5.41 (1H, d, J 4.9 Hz).

(b) t-Butyl7β-[N-2,2,2-trichloroethoxycarbonyl-N-nonafluorobutanesulphonylamino]cephalosporanate

t-Butyl 7β-(nonafluorobutanesulphonylamino)cephalosporanate (200 mg;0.33 mmol) was dissolved in dry MDC (5 ml), cooled to -10° C. andtrichloroethylchloroformate (140 mg; 0.66 mmol) added, followed bypyridine (35 mg; 0.36 mmol). The reacton mixture was poured into ethylacetate-dilute hydrochloric acid. The organic phase was separated,washed with brine, saturated sodium hydrogencarbonate, brine, dried(MgSO₄) and evaporated. Chromatography on silica gel gave the titlecompound (222 mg; 86%). ν_(max) (Nujol) 1790, 1745, 1710, 1615 cm⁻¹ ;δppm (CDCl₃) 1.55 (9H, s), 2.09 (3H, s), 3.47 (2H,AA'), 4.85 and 5.12(2H, ABq, J 13.5 Hz), 4.85 and 4.97 (2H, ABq, J 11.7 Hz), 5.06 (1H, d, J4.82), 5.65 (1H, d, J 4.8 Hz).

(c) t-Butyl 7α-Formamido-7β-[N,2,2,2-trichloroethoxycarbonylamino-]cephalosporanate

t-Butyl7β-[N-2,2,2-trichloroethoxycarbonyl-N-nonafluorobutanesulphonylamino]-cephalosporanate(100 mg; 0.127 mmol) was dissolved in dry MDC (2 ml), cooled to -10° C.and bis-tri(methylsilyl)formamide (26 mg; 0.5 mmol) added, followed bytriethylamine (14 mg; 0.139 mmol). The cooling bath was removed and thereaction warmed to room temperature over 1.75 h. The reaction was pouredinto ethyl acetate, washed with dilute hydrochloric acid, brine, dried(MgSO₄) and evaporated. Chromatography on silica gel afforded the titleproduct (47 mg; 68%) containing 20% t-butyl3-acetoxymethyl-7α-formamido-7β-(N-2,2,2-trichloroethoxycarbonylamino)-ceph-2-em-4-carboxylate.

EXAMPLE 29 (a) t-Butyl7β-(N-4-nitrophenylsulphonylamino)cephalosporanate

t-Butyl 7-aminocephalosporanate (1.48 g) was treated with4-nitrophenylsulphonyl chloride using the procedure described in Example18(A). The title compound (1.6 g) was a crystalline solid m.p. 217°-219°C.(dec). ν_(max) (Nujol) 1795, 1740, 1700, 1630, 1514, 1470, 1350, 1160cm⁻¹ ; δ(1:1, CDCl₃ :(CD₃)₂ SO) 1.45 (9H, s), 1.99 (3H, s), 3.26 and3.53 (2H, ABq, J 18 Hz), 4.67 and 4.96 (2H, ABq, J 14 Hz), 4.93 (1H, d,J 5 Hz), 5.33 (1H, dd, J 5 Hz and 10 Hz), 8.13 and 8.37 (4H, ABq, J 9Hz).

(b) t-Butyl7β-(N-2,2,2-trichloroethyloxycarbonyl-N-4-nitrophenylsulphonylamino)cephalosporanate

t-Butyl 7β-(N-4-nitrophenylsulphonylamino)cephalosporanate (513 mg) wasconverted into the title compound (640 mg) as described in Example18(b). m.p. 136°-137° C., ν_(max) (CHCl₃) 1790, 1742 (broad), 1535, 1170cm⁻¹ ; δ(CDCl₃) 1.54 (9H, s), 2.05 (3H, s), 3.47 (2H, AA'), 4.72 (2H,s), 4.78 and 5.08 (2H, ABq, J 13 Hz), 5.1 (1H, d, J 5 Hz), 5.88 (1H, d,J 5 Hz) 8.34 (4H, AA'). (Found: C, 40.3; H, 3.6; N, 6.2; S, 9.1, Cl,15.5. C₂₃ H₂₄ N₃ O₁₁ S₂ Cl₃ requires C,40.1; H, 3.5; N, 6.1; S, 9.3; Cl,15.5%).

(c) t-Butyl7β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamido-cephalosporanate

t-Butyl7-β-(N-2,2,2-trichloroethoxycarbonyl-N-4-nitrophenylsulphonylamino)cephalosporanate(138 mg) was dissolved in dry dichloromethane (3 ml) at 0° C. andbis-tri(methylsilyl)formamide (160 mg) added, followed by triethylamine(20 mg). The cooling-bath was removed. After 7 h the reaction mixturewas worked up and chromatographed as described in Example 18(c) to givea product (11 mg) consisting of the title compound (40%) and t-butyl3-acetoxymethyl-7-β-(2,2,2-trichloroethoxycarbonylamino)-7α-formamido-ceph-2-em-4-carboxylate(60%).

EXAMPLE 30 (a) Benzyl6β-(2,4,5-trichlorophenylsulphonylamino)penicillanate

Benzyl 6-aminopenicillanate (generated from benzyl 6-aminopenicillanate,p-toluenesulphonic acid salt [2.39 g]) was converted into the titlecompound (1.78 g) as described in Example 18(a); ν_(max) (CHCl₃) 1790,1740, 1360, 1175 cm⁻¹ ; δ(CDCl₃). 1.39 (3H, s), 1.58 (3H, s), 4.41 (1H,s), 5.08 (1H, dd, J 4 and 10 Hz), 5.15 (2H, s), 5.48 (1H, d, J 4 Hz),5.93 (1H, d, J 10 Hz, exch.D₂ O), 7.34 (5H, s), 7.63 (1H, s), 8.15 (1H,s).

(b) Benzyl6β-(N-2,2,2-trichloroethoxycarbonyl-N-2,4,5-trichlorophenylsulphonylamino)penicillanate

Benzyl 6β-(2,4,5-trichlorophenylsulphonylamino)pencillanate (1.099 g)was converted into the title compound (1.363 g) as described in Example18(b); ν_(max) (Nujol) 1805, 1790, 1745, 1380, 1160 cm⁻¹ ; δ(CDCl₃) 1.43(3H, s), 1.67 (3H, s), 4.55 (1H, s), 4.62 and 4.81 (2H, ABq, J 12 Hz),5.19 (2H, s), 5.58 (1H, d, J 4 Hz), 5.92 (1H, d, J 4 Hz) 7.35 (5H,s),7.63 (1H, s), 8.32 (1H, s).

(c) Benzyl6α-formamido-6β-(2,2,2-trichloroethoxycarbonylamino)penicillanate

Benzyl6β-(N-2,2,2-trichloroethoxycarbonyl-N-2,4,5-trichlorophenylsulphonylamino)penicillanate(182 mg) was treated with bis-(trimethylsilyl)formamide (190 mg) andtriethylamine (38 mg). After 71/2 h at room temperature the solution wasworked up as in Example 18(c). Chromatographed on silica gel affordedthe title compound (21 mg), identical to authentic material.

EXAMPLE 31 (a) Benzyl 6β-(p-toluenesulphonylamino)penicillate

Benzyl 6-aminopenicillanate, p-toluenesulphonic acid salt (2.39 g) wassuspended in dichloromethane (25 ml) at -20° C. and triethylamine (1.11g) added, followed by p-toluenesulphonyl chloride (1.05 g). The solutionwas allowed to warm to room temperature. After 70 h the reaction mixturewas poured into ethyl acetate and the solution washed successively withdilute hydrochloric acid, brine, aqueous sodium hydrogen carbonate,brine, dried and evaporated. Chromatography on silica gel gave the titlecompound (1.25 g; ν_(max) (CDCl₃), 1790, 1740, 1350, 1160 cm⁻¹ ;δ(CDCl₃) 1.32 (3H, s), 1.52 (3H, s), 2.39 (3H, s), 4.38 (1H, s), 5.02(1H, dd, J 4 and 11 Hz), 5.29 (1H, d, J 4 Hz), 5.48 L (1H, d J 11 Hz),7.25 (2H, d, J 8 Hz) 73, (5H, s) 7.72 (2H, d, J 8 Hz).

(b) Benzyl6β-(N-2,2,2-trichloroethoxycarbonyl-N-p-toluenesulphonylamino)penicillanate

Benzyl 6β-(p-toluenesulphonylamino)penicillanate (920 mg) was convertedinto the title compound (1.0 g) as described in Example 18(b); ν_(max)(CDCl₃) 1790, 1745, 1380, 1160 cm⁻¹ ; δ(CDCl₃), 1.31 (3H, s), 1.64 (3H,s,), 2.42 (3H, s), 4.52 (1H, s), 4.62 and 4.78 (2H, ABq, J 12 Hz) 5.16(2H, s), 5.55 (1H, d, J 4 Hz), 5.66 (1H, d, J 4 Hz), 7.25 (2H, d, J 8Hz), 7.89 (2H, d, J 8 Hz).

(c) Benzyl6β-(N-2,2,2-trichloroethoxycarbonyl-N-p-toluenesulphonylamino)penicillanate-1-α-oxide

Benzyl6β-(N-2,2,2-trichloroethoxycarbonyl-N-p-toluenesulphonylamino)penicillanate(318 mg) was dissolved in dichloromethane (5 ml) at -10° C. andperacetic acid (0.8 ml of 2.54% W/V solution in acetic acid) added. Thetemperature was raised to +10° and after 3 h the solution was evaporatedto dryness. Toluene was added and the process was repeated (×3). Theresidue was chromatographed on silica gel to give the title compound(221 mg); ν_(max) (CHCl₃) 1805, 1745(broad), 1385, 1170, 1060(broad)cm⁻¹ ; δ(CDCl₃), 1.28 (3H, s), 1.65 (3H, s), 2.40 (3H, s) 4.44 (1H, s),4.68 (2H, s), 4.77 (1H, d, J 4 Hz) 5.22 (2H, AA'), 6.00 (1H, d, J 4 Hz)7.3 (2H, d, J 8.5 Hz). 7.88 (2H, d, J 8.5 Hz).

(d) Benzyl6β-(2,2,2-trichloroethoxycarbonylamino)-6α-formamidopenicillanate-1-α-oxide

Benzyl6β-(N-2,2,2-trichloroethoxycarbonylamino-N-p-toluenesulphonylamino)penicillanate-1-α-oxide(65 mg) was dissolved in dichloromethane (3 ml) andbis-(trimethylsilyl)formamide (76 mg) was added, followed bytriethylamine (10 mg). After 20 min the solution was worked up as inExample 18(c). Chromatography on silica gel gave the title compound (22mg) identical to an authentic sample.

EXAMPLE 31 Benzyl6α-formamido-6β-[D-2-(4-nitrobenzyloxycarbonylamino)-2-phenylacetamido]penicillanate

Silver acetate (0.867 g, 5.2 mmol) was added in one portion to asolution of benzyl6α-methylthio-6β-[D-2-(4-nitrobenzyloxycarbonylamino)-2-phenylacetamido]penicillanate(3.46 g, 5.2 mmol) and N,N-bis(trimethylsilyl)formamide (1.98 g, 10.4mmol) in N,N-dimethylformamide (40 ml), and the reaction mixture wasstirred at room temperature for 0.5 h. It was then diluted with ethylacetate (˜100 ml), filtered through a pad of Celite, and the filtratewas washed with water (5×30 ml). After washing with brine (30 ml), theorganic solution was dried over magnesium sulphate and then evaporatedto dryness to afford the crude product. This was chromatographed onsilica gel 60 (<230 mesh ASTM) eluting with hexane/ethyl acetate 1:1grading to 1:2, to afford the title compound (1.79 g, 52%); ν_(max) (CH₂Cl₂) 1785, 1740, 1690, 1605 cm⁻¹ ; δ(CDCl₃) 0.93 and 1.17 (6H, 2s,2--CH₃ s), 4.41 (1H, s, 3--H), 5.16 L (4H, s, ArCH₂), 5.64 (2H, m,--CHNHCO and 5--H), 6.89 (1H, s, NH), 7.39 (12H, m, aromatic protons),8.14 (3H, m, aromatic protons and CHO) and 8.85 (1H, m, NH).

I claim:
 1. A process for the preparation of a compound of formula (III)or a salt thereof: ##STR27## wherein R¹ is an acyl group, R² is hydrogenor a readily removable carboxyl protecting group; and Y is ##STR28##wherein Y^(o) is sulphur, SO or SO₂, Y¹ is oxygen, sulphur, SO, SO₂ or--CH₂ -- and Z represents hydrogen, halogen, or an organic group such asC₁₋₄ alkoxy, --CH₂ Q or --CH═CH--Qwherein Q represents hydrogen,halogen, hydroxy, mercapto, cyano, carboxy, carbamoyloxy, carboxylicester, C₁₋₄ alkyloxy, acyloxy, aryl, heterocyclyl group bonded viacarbon, a heterocyclylthio group or a nitrogen containing heterocyclicgroup bonded via nitrogen, which process comprises treating anintermediate imine of formula (IV): ##STR29## wherein any reactivegroups may be protected; R¹ and Y are as hereinbefore defined; and R^(x)is a readily removable carboxy protecting group; with a nucleophilicderivative of formamide and thereafter, if necessary, carrying out oneor more of the following steps: (i) removing any protecting groups; (ii)converting a group R^(x) to a group R² ; (iii) converting one group Zinto a different group Z; (iv) converting the product into a salt.
 2. Aprocess as claimed in claim 1wherein the nucleophilic derivative offormamide is an N,N-bis(tri-loweralkylsilyl)formamide.
 3. A processaccording to claim 1wherein the nucleophilic derivative of formamide isN,N-bis-trimethylsilylformamide.
 4. A process as claimed in claim1wherein Y is ##STR30## wherein Y² is oxygen, sulphur or --CH₂ --.
 5. Aprocess as claimed in claim 1wherein Y is --S--C(CH₃)₂ --.
 6. A processas claimed in claim 1 for the preparation of a compound of formula (V)or a pharmaceutically acceptable salt or in vivo hydrolysable esterthereof: ##STR31## wherein R³ is a group such that R³ --CO--NH-- is anacylamino group.
 7. A process as claimed in claim 1 for the preparationof a compound of formula (VI) or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof: ##STR32## wherein R⁸ is phenyl,substituted phenyl, cyclohexenyl, cyclohexadienyl, or a 5- or 6-memberedheterocyclic ring containing up to three hetero-atoms selected fromoxygen, sulphur or nitrogen, optionally substituted with hydroxy, amino,halogen, substituted amino or C₁₋₆ alkoxy; R⁹ is hydrogen or a C₁₋₆alkyl group and R¹⁰ is an optionally substituted 5- or 6-memberedheterocyclic group containing one or two nitrogen heteroatoms; or R⁹ andR¹⁰ together with the nitrogen atom to which they are attached form anoptionally substituted five or six-membered heterocyclic groupcontaining one or two nitrogen heteroatoms.
 8. A process as claimed inclaim 1 for the preparation of a compound of formula (VIII) or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof:##STR33## wherein R¹⁴ represents hydrogen, C₁₋₆ alkyl, substitutedalkyl, aryl, or aralkyl; R¹⁵ and R¹⁶ are the same or different andrepresent hydrogen, C₁₋₆ alkyl, substituted alkyl, halogen, amino,hydroxy or C₁₋₆ alkoxy or R¹⁵ and R¹⁶ form the residue of 5- or6-membered carbocyclic or heterocyclic ring.
 9. A process is claimed inclaim 1 for the preparation of sodium6β-[D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-dihydroxyphenyl)acetamido]-6α-formamidopenicillanate.